Effect of malotilate on chronic liver injury induced by carbon tetrachloride in the rat.

International audienceThe effect of malotilate, a new drug proposed for the treatment of chronic liver diseases, was studied in carbon tetrachloride (CCl4)-induced chronic liver injury in the rat. Treatment with CCl4 (0.5 ml/kg twice per week, intraperitoneally for 6 or 9 weeks) led to marked necrosis, steatosis and fibrosis, as shown by both biochemical and histological examinations, and a significant decrease of the bromosulfophtaleine (BSP) clearance test. Malotilate (50 mg/kg p.o., 5 days per week given simultaneously with CCl4 for 6 weeks), suppressed the increase of plasma aminotransferase activity and decreased significantly the accumulation of lipid and collagen in the liver; histology confirmed this protective effect of malotilate. The BSP clearance test returned to normal values and the rise in hepatic collagen synthesis activity in the malotilate-treated and intoxicated rats was reduced as compared with intoxicated control rats. The same effect was found when malotilate (100 mg/kg, p.o., 5 days per week), was given for 3 weeks to rats already intoxicated during the 6 previous weeks. Malotilate was able to prevent the increase of hepatic alterations that appeared during the last 3 weeks of CCl4 intoxication. These results show clearly that malotilate can markedly reduce the hepatic disorders induced by a chronic CCl4 intoxication in the rat.The effect of malotilate, a new drug proposed for the treatment of chronic liver diseases, was studied in carbon tetrachloride (CCl4)-induced chronic liver injury in the rat. Treatment with CCl4 (0.5 ml/kg twice per week, intraperitoneally for 6 or 9 weeks) led to marked necrosis, steatosis and fibrosis, as shown by both biochemical and histological examinations, and a significant decrease of the bromosulfophtaleine (BSP) clearance test. Malotilate (50 mg/kg p.o., 5 days per week given simultaneously with CCl4 for 6 weeks), suppressed the increase of plasma aminotransferase activity and decreased significantly the accumulation of lipid and collagen in the liver; histology confirmed this protective effect of malotilate. The BSP clearance test returned to normal values and the rise in hepatic collagen synthesis activity in the malotilate-treated and intoxicated rats was reduced as compared with intoxicated control rats. The same effect was found when malotilate (100 mg/kg, p.o., 5 days per week), was given for 3 weeks to rats already intoxicated during the 6 previous weeks. Malotilate was able to prevent the increase of hepatic alterations that appeared during the last 3 weeks of CCl4 intoxication. These results show clearly that malotilate can markedly reduce the hepatic disorders induced by a chronic CCl4 intoxication in the rat

Morphine 6-Glucuronide and Morphine 3-Glucuronide As Molecular Chameleons with Unexpected Lipophilicity

Morphine 6-glucuronide, but not morphine 3-glucuronide, is a highly potent opiate receptor agonist. In fact, there is converging evidence that much of the analgesic effect occurring after morphine treatment in humans is due to this metabolite rather than to the parent drug. Yet glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier and rapidly excreted by the urinary and/or biliary routes. Here, we report that morphine 6-glucuronide, and to a lesser extent morphine 3-glucuronide, are far more lipophilic than predicted, and in fact not much less lipophilic than morphine itself. Force-field and quantum mechanical calculations indicate that the two glucuronides can exist in conformational equilibrium between extended and folded forms. The extended conformers, because they efficiently expose their polar groups, must be highly hydrophilic forms predominating in polar media such as water; in contrast, the folded conformers mask part of their polar groups, thus being more lipophilic and likely to predominate in media of low polarity such as biological membrane

Ghrelin control of GH secretion and feeding behaviour: the role of the GHS-R1a receptor studied in vivo and in vitro using novel non-peptide ligands

Journal Article Research Support, Non-U.S. Gov't Italy EwdEnergy homeostasis is controlled by a complex regulatory system of molecules that affect food intake and that are critical for maintaining a stable body weight during life. Ghrelin is a peptide of 28 amino acid synthesized predominantly by the stomach and the gut, which activate the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a), a G-protein coupled receptor. The acylated form of ghrelin potently stimulates GH secretion both in vitro and in vivo in several animal species, including humans. Beside the endocrine effect, ghrelin shows also extraendocrine activities, including stimulation of feeding behaviour. Several classes of small synthetic peptide and non-peptide ligands of the GHS-R1a have been described and are able to release GH and stimulate food intake. However, in time, it appeared that the stimulating effects on GH secretion could be divorced from those on food intake, suggesting that more than a single receptor might be involved. Several experimental data have even questioned the physiological role of ghrelin in the control of GH secretion and energy metabolism. By using novel agonists, partial agonists, and antagonists for the GHS-R1a receptor, we have studied whether the stimulation of this receptor could account for the purported physiological role of ghrelin. Our results demonstrate that the ability to bind in vitro the GHS-R1a is not predictive of the in vivo biological activity of the compounds and that the endocrine and extraendocrine effects could be mediated also by receptors different from the GHS-R1a

Ghrelin control of GH secretion and feeding behaviour: the role of the GHS-R1a receptor studied in vivo and in vitro using novel non-peptide ligands

Journal Article Research Support, Non-U.S. Gov't Italy EwdEnergy homeostasis is controlled by a complex regulatory system of molecules that affect food intake and that are critical for maintaining a stable body weight during life. Ghrelin is a peptide of 28 amino acid synthesized predominantly by the stomach and the gut, which activate the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a), a G-protein coupled receptor. The acylated form of ghrelin potently stimulates GH secretion both in vitro and in vivo in several animal species, including humans. Beside the endocrine effect, ghrelin shows also extraendocrine activities, including stimulation of feeding behaviour. Several classes of small synthetic peptide and non-peptide ligands of the GHS-R1a have been described and are able to release GH and stimulate food intake. However, in time, it appeared that the stimulating effects on GH secretion could be divorced from those on food intake, suggesting that more than a single receptor might be involved. Several experimental data have even questioned the physiological role of ghrelin in the control of GH secretion and energy metabolism. By using novel agonists, partial agonists, and antagonists for the GHS-R1a receptor, we have studied whether the stimulation of this receptor could account for the purported physiological role of ghrelin. Our results demonstrate that the ability to bind in vitro the GHS-R1a is not predictive of the in vivo biological activity of the compounds and that the endocrine and extraendocrine effects could be mediated also by receptors different from the GHS-R1a

Ghrelin control of GH secretion and feeding behaviour: the role of the GHS-R1a receptor studied in vivo and in vitro using novel non-peptide ligands

Journal Article Research Support, Non-U.S. Gov't Italy EwdEnergy homeostasis is controlled by a complex regulatory system of molecules that affect food intake and that are critical for maintaining a stable body weight during life. Ghrelin is a peptide of 28 amino acid synthesized predominantly by the stomach and the gut, which activate the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a), a G-protein coupled receptor. The acylated form of ghrelin potently stimulates GH secretion both in vitro and in vivo in several animal species, including humans. Beside the endocrine effect, ghrelin shows also extraendocrine activities, including stimulation of feeding behaviour. Several classes of small synthetic peptide and non-peptide ligands of the GHS-R1a have been described and are able to release GH and stimulate food intake. However, in time, it appeared that the stimulating effects on GH secretion could be divorced from those on food intake, suggesting that more than a single receptor might be involved. Several experimental data have even questioned the physiological role of ghrelin in the control of GH secretion and energy metabolism. By using novel agonists, partial agonists, and antagonists for the GHS-R1a receptor, we have studied whether the stimulation of this receptor could account for the purported physiological role of ghrelin. Our results demonstrate that the ability to bind in vitro the GHS-R1a is not predictive of the in vivo biological activity of the compounds and that the endocrine and extraendocrine effects could be mediated also by receptors different from the GHS-R1a